6-bromo-1, 2, 3, 4, 4alpha, 9, 10, 10alpha-octahydro-7-isopropyl-4alpha-methylphenanthrene ketones



ijnited States Patent 6-BROMO -1,2,3,4,4a,9,10,10a OCTAHYDRO-7-ISO- PROPYL 4a METHYLPHENANTHRENE KE- TUNES Robert P. Jacobsen, Shrewsbury, Mass., assignor, by mesne assignments, to G. D. Searle & (10., Skokie, 111., a corporation of Delaware No Drawing. Application October 22, 1953, Serial No. 387,792

3 Claims. (Cl. 260-586) This invention relates to halogenated alkyl-substituted octahydrophenanthrene ketones and processes for the preparation thereof. More particularly, this invention relates to 6-halo-1,2,3,4,4a,9,10,l0a-octahydro-7-isopropyl-4a-methylphenanthrene ketones having the formula CH3 l CH(CH3)2 wherein X is a halogen atom, and Z represents two hydrogen atoms individually bonded to the carbon atom in position 9, or a single oxygen atom doubly bonded to the aforesaid C9 carbon.

it will be recognized that the subject compounds can and do exist in various stereoisomeric configurations. Thus, rings A and B may, alternatively, be cis or trans, one to the other; and each of these forms, in turn occur in either of two enantiomorphic (and optically active) modifications or a racemic combination of these modifications.

The compounds to which this invention relates are useful in medicine as hormonal agents. Especially, the instant compounds are of value in the treatment of various non-androgenic dysfunctions associated With adrenocorticoid imbalance. Thus, for example, being possessed of a potent myotrophic activity uncomplicated by the capacity for testoid stimulation which characterizes and delimits the anabolic utility of testosterone and other naturally-occurring substances known to increase muscle strength and mass, the compounds of this invention are uniquely adapted to use in the care of premature infants, the management of convalescence from acute illness and surgical procedures, and for long-term administration to patients with chronic debilitating disease.

Additionally, the subject compounds are useful as intermediates in the synthesis of other therapeutically interesting materials. Thus, one of the compounds of this invention, a 6-bromo-1,2,3,4,4a,9,l0,10a-octahydro-7-isopropyl 4a-methyl-l-oxophenanthrene having the formula Br a l may be converted to the corresponding 6-bromo- 1,2,3,4,4a,9,10,10a-octahydro 1 hydroxy-7-isopropyl-4amethylphenanthrene, a useful hormonal substance, by treatment with a reducing agent such as aluminum isopropoxide in isopropyl alcohol, or lithium aluminum hydride in a solvent such as diethyl ether. The alurni num isopropoxide reduction is carried out by refluxing an isopropyl alcohol solution of the starting ketone in the presence of an excess of reducing agent, provision being made for slowly distilling off the acetone formed in process through a suitable column. When a test portion of the distillate thus obtained no longer gives a precipitate of acetone dinitrophenylhydrazone on mixing with an aqueous solution of 2,4-dinitrophenylhydrazine, the reduction is complete and the reaction mixture is thereupon worked up by dilution with water and addition of sufiicient hydrochloric acid, sodium hydroxide,-or sodium potassium tartrate to dissolve the precipitate of aluminum hydroxide which forms. An ether extraction is then carried out; and finally the extract is consecutively washed, dried, and concentrated to provide the desired l-hydroxy compound as a residue. Further purification may be effected by distillation in vacuo. The alternative reduction using lithium aluminum hydride takes place in refluxing ether, the starting ketone being added to the hydride solution in dropwise fashion. After a suitable reflux period, the reaction mixture is worked up as hereinafter described (Example 1A) for the lithium aluminum hydride reduction of methyl 6-bromodehydroabietate. The 6-bromo-l,2,3,4,4a,9,10,10a-octahydro-1-hydroxy-7- isopropyl-4a-methylphenanthrene thus obtained is not only valuablein itself, but serves also as a starting point for the synthesis of another chemotherapeutically useful substance, a 6-bromo-1,2,3,4,4a,9,l0,lOa-octahydro-lhydroxy-7-isopropyl-4a-methyl-9-oxophenanthrene. The latter product is prepared by acetylation of the foregoing alcohol according to conventional techniques, followed may be converted to the corresponding 6-bromo l,2,3,4,4a,9,10,10a-octahydro 1,9 dihydroxyJ-isopropyl- 4a-methylphenanthrene. This diol, in turn, may be selectively oxidized to a 6-bromo-1,2,3,4,4a,9,10,10a-oetahydro-9-hydroxy-7-isopropyl 4a methyl-l-oxophenanthrene, which, like the alcohol from which it is made, is also a potent hormonal agent.

The foregoing hydroxy and hydroxyoxo compounds, for the preparation of which the ketones of this invention serve as useful intermediates, may also be beneficially obtained in the form of their lower alkyl, phenyl, and

benzyl ethers. The latter compounds are synthesized by conventional means from the appropriate starting alcohol, for example, by'treatment thereof with lower alkyl or selected aryl halides or with di-lower-alkyl sulfates, as indicated, in the presence of alkali.

The compounds of this invention are soluble in alcohol, as also in propylene gylcol. They may be administered in solid form as tablets or capsules; dissolved or suspended in aqueous alcohols, they may be given parenterally.

A preferred starting material for synthesis of the compounds to which this invention relates is methyl 6-bror'nodehydroabietate, which may be prepared according to the method of Campbell and Morgana, Journal of the American Chemical Society, 63, 1838 (1941). This material is reacted with a reducing agent, such as lithium aluminum hydride, in an inert solvent, to give 6-bromo-l,2,3, 4, 4a,9,'l0,lQa octahydro 7 isopropyl 1,4a dimethylphenanthrene l methanol (6 bromodehydroabietinol) The latter substance, upon treatment with phosphorus pentachloride, phosphorus pentoxide, or the equivalent, undergoes dehydration-rearrangement to an ethylidene compound of the formula The ethylidene compound is, in turn, oxidized, as for example by ozonolysis, to give a 6-bromo-l,2,3,4,4a,9,l0, 10a octahydro 7 isopropyl 4a methyl 1 oxophenanthrene. The monoketones thus represented, all compounds of the present invention may be converted to the corresponding diketones of this invention by mild chromic acid oxidation or the equivalent.

The following examples will illustrate in detail certain of the compounds which constitute the present invention, and methods which have been devised for their preparation. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. In the examples hereinafter detailed, temperatures are given in degrees centigrade C.), pressures in millimeters (mm.) of mercury, and relative amounts of materials in parts by Weight, except as otherwise noted.

Example 1 A. 6 bromo 1 ethylidene 1,2,3,4,4a,9,10,10a -ctahydro 7 isopropyl 4a methylphenanthrene.-Methyl 6-bromodehydroabietate, prepared according to the meth- 0d of Campbell and Morgana, loc. cit., is converted to a 6 bromo 1,2,3,4,4a,9,l0,10a octahydro 7 isopropyl l,4a dimethylphenanthrene 1 methanol (6 bromodehydroabietinol) by reduction of 125 parts thereof with 10 parts of lithium aluminum hydride in 475 parts of anhydrous ether. The starting ester-being only slightly soluble in etheris incorporated in the .reaction mixture by continuous extraction, using a modified Soxhlet apparatus. Work-up of the reaction mixture proceeds through. dropwise addition of suflicient ethyl acetate to react with excess hydride, after which water is. cautiously introduced until hydrogen evolution ceases,

and finally the cooled suspension obtained at this point is acidified with dilute hydrochloric acid. The ether layer is separated and consecutively washed with water, dilute aqueous sodium bicarbonate, and saturated aqueous sodium chloride. Solvent is stripped, and the residue is then crystallized from aqueous methanol. The 6 bromo l,2,3,4,4a,9,l0,10a octahydro 7 isopropyl 1,4a dimethylphenanthrene 1 methanol thus prepared has a melting point of approximately 116 C. A solution of 20 parts of this material in parts of anhydrous benzene is added to a stirred, boiling suspension of 20 parts of phosphorus pentoxide in 130 parts of commercial n-hexane which has been preliminarily treated by repeated boiling with (fresh) phosphorus pentoxide and subsequent distillation to the point where essentially no color develops in the boiling hexane-phosphorus pentoxide suspension. When the addition of carbinol is complete, the reaction mixture is cooled; and the spent dehydrating agent is allowed to settle out. The supernatant hexane solution is decanted and the residue then washed superficially with (fresh) n-hexane, these washings being added to the decanted material. The hexane. solution is allowed to stand with intermittent agitation in contact with an aqueous slurry of sodium bicarbonate until free of acid, whereupon it is separated, shaken with anhydrous sodium bicarbonate, filtered, and stripped of solvent under reduced pressure, in that order. Vacuum distillation of the oily residue afiords a hydrocarbon mixture, B. P. l44-148 C. at 0.03 mm. pressure and [a] +2O8, one constituent of which is 6-bromo-l-ethylidene-1,2,3, 4,4a,9,l0,l0a octahydro 7 isopropyl 4a methylphenanthrene.

B. 6 bromo 1,2,3,4,4a,9,10,10a octahydro 7 is0pr0pyl-4a-methyl-1-0x0phenanthrene semicarbaz0ne. A solution of approximately 28 parts of the ethylidenecontaining hydrocarbon of the preceding part A in approximately 370 parts of methyl acetate is treated at 75 C. for approximately 3 hours with oxygen containing 4% ozone. The desired ozon'ide thus formed has the formula The reaction mixture is steam distilled to remove solvent and decompose the ozonide, whereupon the distilland is extracted with ether. The extract, after being washed with dilute aqueous sodium bicarbonate and then dried over an hydrous sodium sulfate, is stripped of solvent. The residual oil thus obtained is refluxed for 2 hours with methanolic s'emicarbazide prepared as follows: 26 parts of semicarbazide hydrochloride and 12 parts of anhydrous sodium carbonate is triturated with succeeding portions of methyl alcohol until carbon dioxide evolution ceases; the combined supernatants are filtered; 2.6'p arts of glacial acetic acid is added to the filtrate; and, finallyQthe filtrate volume is brought to approximately times that of the added acid, with methyl alcohol. Precipitation occurs during the reflux period. The cooled reaction mixture is poured into approximately 3 volumes of well-stirred cold water, whereupon the precipitated solid is, successively, collected, washed with water, and dried in air. Repeated extraction of this material with small volumes of methyl alcohol ieaves the desired semicarbazone as a sparingly soluble residue which, recrystallized from chloroform, shows M. P. approximately 262 (3., [041 +212. The 6 bromo l,2,3,4,4a,9,l0,l0a octahydro 7 isopropy1-4a-methyl-l-oxophenanthrene semicarbazone thus prepared has the formula Br I NNHOONHQ C. 6 brm0-1,2,3,4,4a,9,10,10a clahydra 7 isopr0pyl-4wmethyl-l-oxophenanthrene.A suspension of 2.5 parts of the semicarbazone of the foregoing part B in 200 parts of methanol is refluxed for 45 minutes with 50 parts of water containing 4 parts or" approximately 20% aqueous hydrochloric acid, nearly complete solution being achieved in process. into cold Water and the resultant mixture extracted with n-pentane. The pentane solution, washed with water, ried over anhydrous sodium sulfate, and stripped of solvent, in that order, affords a 6-br0mo-l,2,3,4,4a,9,10,10aoctahydro-i-isopropyl-4a-methyl-l-oxophenanthrene as a solid residue, which, crystallized from methyl alcohol,

shows M. P. 130-132" C., [0:1 +135.

Example 2 6 brOmo 1,2,3,4,4a,9,10,10a octahydro 7 isopr0pyl-4a-mezhyl-1,9-di0x0phenanthrene.-A solution of approximately 3 parts of the bromoketone of Example 16 in 40 parts of acetic acid is cooled and mixed with 13 parts of a chromic acid solution consisting of 1 part chromic anhydride and 4 parts of 80% aqueous acetic acid. The reaction mixture is maintained at about 35 C. for 23 hours, at which point an additional 11 parts of the chromic acid solution is mixed in and the reactants then allowed to stand at the 35 temperature for 5- hours longer. Water is then added, following which sufficient aqueous sodium sulfite solution is introduced to neutralize excess chromic acid. The mixture is ex tracted with ether and the extract is washed with Water, dilute aqueous caustic soda, Water, and saturated aqueous sodium chloride, in that order. The ether solution is dried over anhydrous sodium sulfate and, finally, stripped of solvent. Crystallization of the residue from a mixture of ether and n-hexane provides the desired 6 bromo l,2,3,4,4a,9,10,l0a octahydro 7 isopropyl la-methyl-1,9-dioxophenanthrene.

The reactants are poured iii 6 I claim: 1. A compound of the fromula Br CH1 OH(O a)a Br 2 I o 3. A 6-bromo-1,2,3,4,4a,9,10,10a-octahydro-7-isopropyl-4a-methy1-1,9-dioxophenanthrene, having the formula Br a l References Cited in the file of this patent Campbell et al.: Jour. Am. Chem. Soc. 63, 1838 (1941).

Cook et al.: Jour. Chem. Soc. 1944, pp. 286-293.

Brossi et al.: Helv. Chirn. Acta, 33, 1730 (1950). 

1. A COMPOUND OF THE FORMULA 